Highlights from Recent Cancer Literature
Journal: Cancer Research (2013)

Herrera-Abreu MT, Pearson A, Campbell J, Shnyder SD, Knowles MA, Ashworth A, et al. Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer. Cancer Discov 2013;3:1058–71.The fibroblast growth factor receptor (FGFR) is activated in cancers through mutation, gene amplification, and/or translocation, signifying that this receptor tyrosine kinase may be a therapeutic target. Herrera-Abreu and colleagues conducted parallel siRNA screens targeting all known protein kinases and phosphatases in a panel of 11 FGFR-aberrant cell lines (with and without treatment with a pan-FGFR inhibitor, PD173074) to elucidate which of the diverse mechanisms of activation of FGFRs are most likely to translate into clinical efficacy. Interestingly, FGFR3-activated cell lines were insensitive to both FGFR3 siRNA and PD173074, suggesting alternative drivers of tumor growth in these cells. Supervised hierarchical clustering identified siRNA against EGFR as sensitizing FGFR3-activated bladder cancer cell lines to PD173074. Other FGFR-driven cell lines were unaffected by siRNA against EGFR, thereby identifying a subtype/mutation-specific event. The authors identified two patterns of response: One group was partially FGFR3 dependent, with EGFR signaling limiting sensitivity to FGFR inhibitors, and the other was primarily EGFR dependent, with intrinsic resistance to FGFR inhibitors. Impaired receptor trafficking reinforced the upregulation of both EGFR and FGFR3. In response to FGFR3 inhibition, EGFR accumulated at the plasma membrane and in early endosomes. Likewise, in response to EGFR inhibition, FGFR3 accumulated at the membrane. They found that inhibition of SRC family kinases with dasatinib resulted in substantial FGFR3 derepression. The authors further investigated pathway inhibition and found that dual MEK and PI3K inhibition derepressed FGFR3, suggesting that EGFR signaling, reinforced by SRC, repressed FGFR3 expression through this combined action. These findings highlight both the potential complexity of therapeutic resistance and the clinical translational challenges of identifying key receptors that drive resistance. EGFR appears to compensate for FGFR inhibition, and dual targeting strategies may be effective in the clinic if EGFR is indeed mediating resistance to mutant FGFR3 targeting in bladder cancer.Tam WL, Lu H, Buikhuisen J, Soh BS, Lim E, Reinhardt F, et al. Protein kinase Cα is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell 2013;24:347–64.Identification of therapeutic targets enriched in cancer stem cells (CSC) has been hampered by the difficulties in identifying and collecting rare CSCs. To overcome these technical hurdles, Tam and colleagues took advantage of the observation that mammary CSCs express many mesenchymal-type properties, presumably because they have undergone an epithelial–mesenchymal transition (EMT) as part of their genesis. Comparing mammary epithelial cells with or without such mesenchymal properties, they identified protein kinase Cα (PKCα, PRKCA) as one such differentially expressed therapeutic candidate. Using four distinct chemical inhibitors, or specific siRNA, they demonstrated that PKCα maintained CSC properties in vitro and in vivo. They also showed that PDGF stimulates PKCα through activation of phospholipase Cγ in these mesenchymal-like epithelial cells. PKCα in turn activated a molecular switch controlled by the FOS family of AP-1 transcription factors, in which FOS or FRA1 were preferentially utilized in non-CSCs or CSCs respectively. Interestingly, components of this signaling pathway were also enriched in basal B and triple-negative primary breast cancers, which have previously been shown to elaborate many EMT-like markers. Consistent with the PKCA signaling pathway functioning as a CSC-enriched therapeutic target, the growth of patient derived, triple-negative xenografts in NOD–SCID mice was attenuated with a PKCα pharmacologic inhibitor. The authors speculate that the EMT CSC program may be used by other carcinoma cell types, potentially extending these findings and targets beyond breast CSCs.Tu Y, Gao X, Li G, Fu H, Cui D, Liu H, MicroRNA-218 inhibits glioma invasion, migration, proliferation, and cancer stem-like cell self-renewal by targeting the polycomb group gene Bmi1. Cancer Res 2013;73:6046–55.Malignant gliomas represent the most common types of CNS tumors and are characterized by high rates of invasiveness, migration, and proliferation. Surgery, radiotherapy. and chemotherapy remain the mainstay treatment options available for patients with advanced disease. Accumulating evidence supports a role for microRNAs in regulating cellular processes. The expression of miR-218 is suppressed in gliomas as compared with normal brain tissue. However, its function in glioma development is largely unknown. In this study, Tu and colleagues show that miR-218 acts as a tumor suppressor in glioma by inhibiting the motility, invasion, proliferation, and stem cell–like characteristics via targeting BMI1, part of the polycomb chromatin remodeling complex of proteins. The in vitro data were substantiated by in vivo findings, wherein miR-218–expressing glioma cells showed remarkable growth inhibition when they were implanted in immunocompromised mice, as compared with the control counterparts. Additionally, miR-218 impaired the self-renewal of glioma stem-like cells by downmodulating BMI1 gene expression. Detailed pathway analysis revealed that miR-218 also regulated several other key genes that could be targets for abrogating glioma development. These findings uncover the potential role of miR-218 overexpression as a strategy for developing an alternative therapy for glioma.Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, et al. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nat Med 2013;19:1114–23.Tumors rely on a vascular supply, and antiangiogenic agents target this dependence. As with most targeted agents, however, resistance to antiangiogenic agents limits their therapeutic effect. Chung and colleagues tested the hypothesis that extracellular factors released by tumor cells can mediate resistance to antiangiogenic agents. By comparing the profile of secreted factors produced by cells sensitive and resistant to VEGF antibody treatment, the authors identified differential expression of IL-17A (referred to as IL-17). In a series of in vivo experiments involving multiple tumor models and a combination of tumor hosts, including T-cell-deficient, IL-17R-null, and G-CSF–null mice, they demonstrate an IL-17-dependent paracrine signaling mechanism of resistance to VEGF antibody treatment. IL-17, produced by T-helper type 17 cells or by tumor cells themselves, can act on tumor-associated fibroblasts to stimulate secretion of proinflammatory and neutrophil-mobilizing cytokines, including G-CSF and IL-6, via activation of the NF-κB and MAPK signaling. These proinflammatory cytokines, in particular G-CSF, recruit immunosuppressive CD11b+Gr1+ myeloid cells and neutrophils to the tumor microenvironment. Influx of these cells and local production of angiogenic factors, including Bv8 (PROK2), promote IL-17-dependent and VEGF-independent angiogenesis. Combination therapy with anti-VEGF and anti-IL-17 antibodies resulted in a superior antitumor response in resistant cell lines. These studies suggest anti-IL-17 therapy as an important addition to antiangiogenic therapies in some patients. Furthermore, these data provide a compelling example of the contribution of the tumor microenvironment to therapy resistance and highlight an important determinant of therapeutic response.Irshad S, Bansal M, Castillo-Martin M, Zheng T, Aytes A, Wenske S, et al. A molecular signature predictive of indolent prostate cancer. Sci Transl Med 2013;5:202ra122.Prostate cancer is classified based on Gleason scoring, which provides a guide for treatment. Ideally, tumors with low Gleason scores should be completely harmless, and those with high scores will progress to lethal metastatic disease. Importantly, whereas some patients with low Gleason scores remain recurrence free, others in this same category will develop life-threatening disease. For these patients, oncologists had no tools to predict recurrence. Irshad and colleagues provide a new set of biomarkers that identify those patients at risk of developing recurrent disease. The authors reasoned that tumors that would produce indolent disseminated disease would be those enriched for aging and senescence genes, and they selected 377 genes for these biologic processes. Using different computational and statistical tools as well as separate sample sets across different continents, they narrowed this signature to 19 genes. This signature was highly predictive in distinguishing low Gleason score patients at risk of developing recurrences from those remaining indolent. Focusing on the group of patients for whom specific prediction markers were absent, the authors further refined the signature to three genes, FGFR1, CDKN1A, and PMP22. This minimal subset of genes had predictive value either at the mRNA or protein level, and the authors provide convincing evidence for the use of these markers as a decision tool in clinical practice. The molecular function by which these genes drive indolent disease is not obvious, as FGF signaling is commonly linked to growth promotion and PMP22 is a nervous system–expressed glycoprotein. CDKN1A is more expected, as it is a powerful growth arrest–inducing CDK inhibitor in multiple processes, including stress responses to damage, differentiation, quiescence, and senescence. Regarding the latter two categories, these genes may define senescent disseminated disease destined never to recur but also quiescent dormant disease that may show late recurrence. Analysis of these genes in disseminated tumor cells in bone marrow and modeling their function may provide further insight into mechanisms distinguishing these different routes for prostate cancer progression.Liu R, Li J, Xie K, Zhang T, Lei Y, Chen Y, et al. FGFR4 promotes stroma-induced epithelial to mesenchymal transition in colorectal cancer. Cancer Res 2013;73:5926–35.The interactions of tumor cells with the surrounding stroma and the extracellular matrix support the growth of tumor cells by providing the survival signals and aid in tumor infiltration to distant sites. Tumor-associated fibroblasts (TAF) are key components and play a crucial role in tumor metastases by inducing epithelial–mesenchymal transition (EMT). In this study, Liu and colleagues explored the involvement of FGFR4 in promoting TAF-induced EMT in colorectal cancer cell lines. Coculture of tumor cells with TAFs resulted in a dramatic increase in the expression of FGFR4. They also found that TAF-derived CCL2 and its downstream transcription factor, ETS1, are required for stimulation of FGFR4. Further experiments revealed the activation and nuclear translocation of β-catenin by upregulated FGFR4. In addition, FGFR4-associated downstream pathways like Wnt signaling were found to be stimulated in colorectal cell lines and mouse metastasis models. FGFR4 also enhanced the migration of colorectal cancer cells, which was reversed upon siRNA-mediated silencing of this growth factor receptor. These data suggest that FGFR4 is a key regulator in promoting EMT and could be used as a target in the context of colorectal cancer.Note: Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.